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Abstract:

Described are palladium precatalysts, and methods of making and using
them. The palladium precatalysts show improved stability and improved
reactivity in comparison to previously-described palladium precatalysts.

2. The precatalyst of claim 1, wherein L is selected from the group
consisting of PPh3, Ph2P--CH3, PhP(CH3)2,
P(o-tol)3, PCy3, P(tBu)3, BINAP, dppb, dppe, dppf, dppp,
##STR00059## ##STR00060## or its salt, ##STR00061## or its salt,
##STR00062## ##STR00063## ##STR00064## Rx is alkyl, aralkyl,
cycloalkyl, or aryl; X1 is CH or N; R3 is H or alkyl; R4
is H, alkoxy, or alkyl; R5 is alkyl or aryl; and n is 1, 2, 3, or 4.

5. The precatalyst of claim 1, wherein R2, where present, is
substituted or unsubstituted alkyl.

6. The precatalyst of claim 1, wherein R2, where present, is
substituted or unsubstituted aryl.

7. The precatalyst of claim 1, wherein the precatalyst is selected from
the group consisting of: ##STR00065## H, alkyl, or aryl; L is selected
from the group consisting of PPh3, Ph2P--CH3,
PhP(CH3)2, P(o-tol)3, PCy3, P(tBu)3, BINAP,
dppb, dppe, dppf, dppp, ##STR00066## ##STR00067## or its salt,
##STR00068## or its salt, ##STR00069## ##STR00070## ##STR00071## Rx
is alkyl, aralkyl, cycloalkyl, or aryl; X1 is CH or N; R3 is H
or alkyl; R4 is H, alkoxy, or alkyl; R5 is alkyl or aryl; and n
is 1, 2, 3, or 4;

8. A dimer of formula XI: ##STR00072## wherein, independently for each
occurrence, X is a non-coordinating anion; and R1 is H, alkyl,
haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and R2 is alkyl,
haloalkyl or aryl.

11. The dimer of claim 8, wherein R2, where present, is substituted
or unsubstituted alkyl.

12. The dimer of claim 8, wherein R2, where present, is substituted
aryl or unsubstituted aryl.

13. (canceled)

Description:

RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional
Patent Application Ser. No. 61/657,377, filed Jun. 8, 2012, the contents
of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0003] Transition metal catalyst complexes play important roles in many
areas of chemistry. Catalyst complexes are recognized to be influenced by
the characteristics of the transition metal and those of the associated
ligands. For example, structural features of the ligands can influence
reaction rate, regioselectivity, and stereoselectivity in reactions
involving the catalyst complexes. For example, in coupling reactions,
electron-withdrawing ligands can be expected to slow oxidative addition
to, and speed reductive elimination from, the metal center; and,
conversely, electron-rich ligands can be expected to speed oxidative
addition to, and slow reductive elimination from, the metal center.

[0004] Although phosphine-ligated Pd(0) complexes constitute the active
catalyst in many reactions, such complexes are usually difficult to
prepare and extremely air-sensitive.
Tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), which was
developed to serve as a stable source of Pd(0), includes coordinating
dibenzylideneacetone ligands that can significantly retard the formation
of the actual active catalyst complex and/or diminish its ultimate
reactivity. The use of a Pd(II) salt, such as Pd(OAc)2, which
circumvents problems of precatalyst instability, requires in situ
reduction in order to generate the active Pd(0) complex. In light of the
complications in forming phosphine-ligated Pd(0) complexes, precatalyst
scaffolds constituting the source of Pd and phosphine ligand were
developed. See FIG. 1. These precatalysts formed the active, monoligated
Pd complex under mild conditions and without the need for exogenous
additives.

[0005] However, working with known precatalysts can be problematic. For
example, the three-step preparation of precatalyst 1 (FIG. 1) involves
the handling of sensitive organometallic intermediates and is not
amenable to large-scale production. Additionally, precatalyst 1 is prone
to decomposition in solution after a few hours and is not compatible with
bulkier ligands, such as tBuBrettPhos, RockPhos, AdBrettPhos, and
Me4tBuXPhos. See FIG. 10. Precatalyst 2, which can be prepared
relatively simply, is not widely suitable; for example, it cannot be
formed with bulkier ligands, such as BrettPhos, tBuXPhos, tBuBrettPhos,
RockPhos, AdBrettPhos, and Me4tBuXPhos; additionally, it does not
exhibit prolonged stability in solution.

[0006] There exists a need for a new class of air-stable, moisture-stable,
solution-stable, one-component Pd precatalysts that may be activated
under standard reaction conditions and ensures the formation of the
active complex, L1Pd(0), with a wide range of ligands.

SUMMARY OF THE INVENTION

[0007] In certain embodiments, the invention relates to a precatalyst of
formula I

[0041] FIG. 1 depicts two known precatalysts. The stereochemistry at Pd in
the precatalysts is cis or trans.

[0042] FIG. 2 depicts a palladium sulfonate dimer of the invention. The
stereochemistry at Pd in the dimer is cis or trans.

[0043] FIG. 3 depicts a palladium sulfonate dimer of the invention. The
stereochemistry at Pd in the dimer is cis or trans.

[0044] FIG. 4 depicts a palladium sulfonate dimer of the invention. The
stereochemistry at Pd in the dimer is cis or trans.

[0045] FIG. 5 depicts a palladium sulfonate dimer of the invention. The
stereochemistry at Pd in the dimer is cis or trans.

[0046] FIG. 6 depicts a general procedure to synthesize a
2-aminobiphenylpalladium mesylate precatalyst of the invention from a
palladium sulfonate dimer of the invention. The stereochemistry at Pd in
the precatalyst and in the dimer is cis or trans.

[0047] FIG. 7 depicts an exemplary synthesis of a 2-aminobiphenylpalladium
mesylate precatalyst from a palladium sulfonate dimer of the invention.
The stereochemistry at Pd in the precatalyst and in the dimer is cis or
trans.

[0048] FIG. 8 tabulates as function of the ligand used the yields of
various 2-aminobiphenylpalladium mesylate precatalysts of the invention
formed from the corresponding palladium sulfonate dimer.

[0049] FIG. 9 depicts an exemplary synthesis of a 2-aminobiphenylpalladium
triflate precatalyst from a palladium triflate dimer of the invention.
The stereochemistry at Pd in the precatalyst and in the dimer is cis or
trans.

[0050] FIG. 10 depicts various ligands that may be used to prepare the
precatalysts of the invention (tBuBrettPhos=L15; AdBrettPhos=L16;
RockPhos=L17).

[0051] FIG. 11 depicts various ligands that may be used to prepare the
precatalysts of the invention.

[0052] FIG. 12 depicts two palladium sulfonate dimers of the invention.
The stereochemistry at Pd in the dimers is cis or trans.

[0053] FIG. 13 depicts an exemplary synthesis of a
2-aminobiphenylpalladium sulfonate precatalyst from
[1,1'-biphenyl]-2-amine. The stereochemistry at Pd in the precatalyst and
in the dimer is cis or trans.

[0059] FIG. 19 depicts an exemplary synthesis of a
2-aminobiphenylpalladium hexafluorophosphate precatalyst from a dimer.
The stereochemistry at Pd in the precatalyst and in the dimer is cis or
trans.

[0060] FIG. 20 depicts an exemplary synthesis of a
2-aminobiphenylpalladium tetrafluoroborate precatalyst from a dimer. The
stereochemistry at Pd in the precatalyst and in the dimer is cis or
trans.

[0061] FIG. 21 depicts an exemplary synthesis of a precatalyst from
N-phenyl-[1',1'-biphenyl]-2-amine. The stereochemistry at Pd in the
precatalyst and in the dimer is cis or trans.

[0062] FIG. 22 depicts an exemplary synthesis of various precatalysts of
the invention. The stereochemistry at Pd in the precatalyst and in the
dimer is cis or trans.

[0063] FIG. 23 depicts the amidation of aryl chlorides using a precatalyst
of the invention. Reaction conditions: K3PO4 and 1%
precatalyst, in tBuOH at 110° C.

[0064] FIG. 24 depicts the fluorination of aryl triflates using a
precatalyst of the invention.

[0065] FIG. 25 depicts the arylation of phenols using a precatalyst of the
invention.

[0066] FIG. 26 depicts the arylation of alcohols using a precatalyst of
the invention.

[0067] FIG. 27 depicts the trifluoromethylation of aryl triflates and an
aryl chloride using precatalysts of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Overview

[0068] In certain embodiments, the invention relates to a palladium
sulfonate precatalyst. In certain embodiments, the synthesis of the
precatalysts may be easily accomplished from commercially available
starting materials. In certain embodiments, the precatalysts incorporate
any of a wide range of phosphine ligands. In certain embodiments, the
precatalysts are markedly stable in solution. In certain embodiments, the
precatalysts are stable in solution for greater than about one month.

Precatalysts of the Invention

[0069] In certain embodiments, the invention relates to a precatalyst of
formula I

[0101] In certain embodiments, the invention relates to a precatalyst of
any one of formulae I, II, III, IV, V, VI, VII, or VIII, wherein L is a
ligand described in U.S. Pat. No. 7,858,784, which is hereby incorporated
by reference in its entirety.

[0102] In certain embodiments, the invention relates to a precatalyst of
any one of formulae I, II, III, IV, V, VI, VII, or VIII, wherein L is a
ligand described in U.S. Patent Application Publication No. 2011/0015401,
which is hereby incorporated by reference in its entirety.

[0103] In certain embodiments, the invention relates to a precatalyst of
any one of formulae I, II, III, IV, V, VI, VII, or VIII, wherein L is
selected from the group consisting of

##STR00017##

and tetramethylethylenediamine (TMEDA).

[0104] In certain embodiments, the invention relates to a precatalyst of
any one of formulae I, II, III, IV, V, VI, VII, or VIII, wherein L is

##STR00018##

and R3 is H or alkyl.

[0105] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein L is selected from the group
consisting of PPh3, Ph3P--CH3, PhP(CH3)2,
P(o-tol)3, PCy3, P(tBu)3, BINAP, dppb, dppe, dppf, dppp,

[0113] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is alkylsulfonate; and the alkyl
is substituted alkyl. In certain embodiments, the invention relates to
any one of the aforementioned precatalysts, wherein X is alkylsulfonate;
and the alkyl is unsubstituted alkyl.

[0114] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is alkylsulfonate; and the alkyl
is methyl, ethyl, propyl, or butyl. In certain embodiments, the invention
relates to any one of the aforementioned precatalysts, wherein X is
alkylsulfonate; and the alkyl is methyl or ethyl.

[0115] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is haloalkylsulfonate. In certain
embodiments, the invention relates to any one of the aforementioned
precatalysts, wherein X is fluoroalkylsulfonate.

[0116] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is fluoromethylsulfonate. In
certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is trifluoromethylsulfonate.

[0117] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is cycloalkylalkylsulfonate. In
certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is

##STR00025##

or its enantiomer.

[0118] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is arylsulfonate; and the aryl is
substituted aryl. In certain embodiments, the invention relates to any
one of the aforementioned precatalysts, wherein X is arylsulfonate; and
the aryl is unsubstituted aryl.

[0119] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein X is phenylsulfonate. In certain
embodiments, the invention relates to any one of the aforementioned
precatalysts, wherein X is methylphenylsulfonate. In certain embodiments,
the invention relates to any one of the aforementioned precatalysts,
wherein X is p-toluenesulfonate.

[0120] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein R1 is H or alkyl. In certain
embodiments, the invention relates to any one of the aforementioned
precatalysts, wherein R1 is H.

[0121] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein R2 is substituted alkyl. In
certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein R2 is unsubstituted alkyl.

[0122] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein R2 is methyl, ethyl, propyl, or
butyl.

[0123] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein R2 is substituted aryl. In
certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein R2 is unsubstituted aryl.

[0124] In certain embodiments, the invention relates to any one of the
aforementioned precatalysts, wherein R2 is phenyl.

[0125] In certain embodiments, the invention relates to a compound
selected from the group consisting of:

##STR00026##

wherein L is selected from the group consisting of PPh3,
P(o-tol)3, PCy3, P(tBu)3, BINAP, dppf, dppp,

##STR00027## ##STR00028##

[0126] In certain embodiments, the invention relates to a compound of the
following structure:

##STR00029##

wherein L is selected from the group consisting of PPh3,
P(o-tol)3, PCy3, P(tBu)3, BINAP, dppf, dppp,

##STR00030##

[0127] In certain embodiments, the invention relates to a compound of the
following structure:

##STR00031##

wherein L is selected from the group consisting of

##STR00032##

[0128] In certain embodiments, the invention relates to a compound of any
one of the following structures:

##STR00033##

wherein

[0129] R is H, alkyl, or aryl; and

[0130] L is any one of the aforementioned ligands.

[0131] In certain embodiments, the invention relates to a compound of any
one of the following structures:

##STR00034##

wherein

[0132] R is H, alkyl, or aryl; and

[0133] L is any one of the aforementioned ligands.

[0134] In certain embodiments, the invention relates to a compound of any
one of the following structures:

##STR00035##

wherein

[0135] R is H, alkyl, or aryl; and

[0136] L is any one of the aforementioned ligands.

Dimers of the Invention

[0137] In certain embodiments, the invention relates to a dimer of formula
IX

[0160] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein X is alkylsulfonate; and the alkyl is
substituted alkyl. In certain embodiments, the invention relates to any
one of the aforementioned dimers, wherein X is alkylsulfonate; and the
alkyl is unsubstituted alkyl.

[0161] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein X is alkylsulfonate; and the alkyl is
methyl, ethyl, propyl, or butyl. In certain embodiments, the invention
relates to any one of the aforementioned dimers, wherein X is
alkylsulfonate; and the alkyl is methyl or ethyl.

[0162] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein X is haloalkylsulfonate. In certain
embodiments, the invention relates to any one of the aforementioned
dimers, wherein X is fluoroalkylsulfonate.

[0163] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein X is fluoromethylsulfonate. In certain
embodiments, the invention relates to any one of the aforementioned
dimers, wherein X is trifluoromethylsulfonate.

[0164] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein X is cycloalkylalkylsulfonate. In certain
embodiments, the invention relates to any one of the aforementioned
dimers, wherein X is

##STR00044##

or its enantiomer.

[0165] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein X is arylsulfonate; and the aryl is
substituted aryl. In certain embodiments, the invention relates to any
one of the aforementioned dimers, wherein X is arylsulfonate; and the
aryl is unsubstituted aryl.

[0166] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein X is phenylsulfonate. In certain
embodiments, the invention relates to any one of the aforementioned
dimers, wherein X is methylphenylsulfonate. In certain embodiments, the
invention relates to any one of the aforementioned dimers, wherein X is
p-toluenesulfonate.

[0167] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein R1 is H or alkyl. In certain
embodiments, the invention relates to any one of the aforementioned
dimers, wherein R1 is H.

[0168] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein R2 is substituted alkyl. In certain
embodiments, the invention relates to any one of the aforementioned
dimers, wherein R2 is unsubstituted alkyl.

[0169] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein R2 is methyl, ethyl, propyl, or
butyl.

[0170] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein R2 is substituted aryl. In certain
embodiments, the invention relates to any one of the aforementioned
dimers, wherein R2 is unsubstituted aryl.

[0171] In certain embodiments, the invention relates to any one of the
aforementioned dimers, wherein R2 is phenyl.

METHODS OF THE INVENTION

[0172] In certain embodiments, the invention relates to a method of Scheme
1:

[0179] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein temperature 1 is from about 50° C.
to about 150° C. In certain embodiments, the invention relates to
any one of the aforementioned methods, wherein temperature 1 is about
55° C., about 60° C., about 65° C., about 70°
C., about 75° C., about 80° C., about 85° C., about
90° C., about 95° C., about 100° C., about
105° C., about 110° C., about 115° C., about
120° C., about 125° C., about 130° C., about
135° C., about 140° C., or about 145° C.

[0180] In certain embodiments, the invention relates to a method of Scheme
2:

[0187] R8 is alkyl, aralkyl, aryl, or heteroaryl, or, R7 and
R8, taken together, form a cycloalkyl or heterocycloalkyl ring;

[0188] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein temperature 2 is from about 40° C.
to about 120° C. In certain embodiments, the invention relates to
any one of the aforementioned methods, wherein temperature 2 is about
45° C., about 50° C., about 55° C., about 60°
C., about 65° C., about 70° C., about 75° C., about
80° C., about 85° C., about 90° C., about 95°
C., about 100° C., about 105° C., about 110° C., or
about 115° C.

[0189] In certain embodiments, the invention relates to a method of Scheme
3:

[0195] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein temperature 3 is from about 10° C.
to about 60° C. In certain embodiments, the invention relates to
any one of the aforementioned methods, wherein temperature 3 is about
15° C., about 20° C., about 25° C., about 30°
C., about 35° C., about 40° C., about 45° C., or
about 50° C.

[0196] In certain embodiments, the invention relates to a method of Scheme
4:

[0201] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein temperature 4 is from about 60° C.
to about 160° C. In certain embodiments, the invention relates to
any one of the aforementioned methods, wherein temperature 4 is about
65° C., about 70° C., about 75° C., about 80°
C., about 85° C., about 90° C., about 95° C., about
100° C., about 105° C., about 110° C., about
115° C., about 120° C., about 125° C., about
130° C., about 135° C., about 140° C., about
145° C., about 150° C., or about 155° C.

[0202] In certain embodiments, the invention relates to a method of Scheme
5:

[0206] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein temperature 5 is from about 70° C.
to about 190° C. In certain embodiments, the invention relates to
any one of the aforementioned methods, wherein temperature 5 is about
75° C., about 80° C., about 85° C., about 90°
C., about 95° C., about 100° C., about 105° C.,
about 110° C., about 115° C., about 120° C., about
125° C., about 130° C., about 135° C., about
140° C., about 145° C., about 150° C., about
155° C., about 160° C., about 165° C., about
170° C., about 175° C., or about 180° C.

[0207] In certain embodiments, the invention relates to a method of Scheme
8:

##STR00050##

wherein, independently for each occurrence,

[0208] the precatalyst is any one of the aforementioned precatalysts;

[0209] X2 is halo;

[0210] Ar1 is aryl or heteroaryl;

[0211] Ar2 is aryl or heteroaryl, which is optionally substituted
with 1, 2, 3, or 4 R11;

[0215] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein temperature 8 is from about 10° C.
to about 90° C. In certain embodiments, the invention relates to
any one of the aforementioned methods, wherein temperature 8 is about
10° C., about 15° C., about 20° C., about 25°
C., about 30° C., about 35° C., about 40° C., about
45° C., about 50° C., about 55° C., about 60°
C., about 65° C., about 70° C., about 75° C., about
80° C., about 85° C., or about 90° C.

[0216] In certain embodiments, the invention relates to a method of Scheme
9:

[0222] R12 is alkyl or substituted alkyl (including but not limited
to aralkyl, fluoroalkylalkyl, or cycloalkylalkyl).

[0223] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein temperature 9 is from about 50° C.
to about 160° C. In certain embodiments, the invention relates to
any one of the aforementioned methods, wherein temperature 9 is about
50° C., about 55° C., about 60° C., about 65°
C., about 70° C., about 75° C., about 80° C., about
85° C., about 90° C., about 95° C., about
100° C., about 105° C., about 110° C., about
115° C., about 120° C., about 125° C., about
130° C., about 135° C., about 140° C., about
145° C., about 150° C., about 155° C., or about
160° C.

[0224] In certain embodiments, the invention relates to a method of Scheme
10:

[0230] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein temperature 10 is from about 50°
C. to about 160° C. In certain embodiments, the invention relates
to any one of the aforementioned methods, wherein temperature 10 is about
50° C., about 55° C., about 60° C., about 65°
C., about 70° C., about 75° C., about 80° C., about
85° C., about 90° C., about 95° C., about
100° C., about 105° C., about 110° C., about
115° C., about 120° C., about 125° C., about
130° C., about 135° C., about 140° C., about
145° C., about 150° C., about 155° C., or about
160° C.

[0233] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 1, solvent 2, solvent 3, or
solvent 4 is a non-polar solvent or a polar aprotic solvent.

[0234] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 1, solvent 2, solvent 3, or
solvent 4 is an ether or an alcohol.

[0235] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 1, solvent 2, solvent 3, or
solvent 4 comprises dioxane, tetrahydrofuran, water, or tBuOH.

[0236] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 5 or solvent 9 is a non-polar
solvent.

[0237] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 5 or solvent 9 comprises toluene.

[0238] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 8 is a non-polar solvent.

[0239] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 8 comprises toluene. In certain
embodiments, the invention relates to any one of the aforementioned
methods, wherein solvent 8 comprises toluene and dimethoxyether.

[0240] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 10 comprises dioxane and toluene.
In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein solvent 10 comprises dioxane and toluene
in a 1:1 ratio.

[0241] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the precatalyst is present in an amount
from about 0.005 mol % to about 10 mol %.

[0242] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the precatalyst is present in about 0.005
mol %, about 0.01 mol %, about 0.05 mol %, about 0.1 mol %, about 0.5 mol
%, about 1 mol %, about 2 mol %, about 3 mol %, about 4 mol %, or about 5
mol %.

[0243] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein L is present in an amount from about
0.005 mol % to about 10 mol %.

[0244] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein L is present in about 0.005 mol %, about
0.01 mol %, about 0.05 mol %, about 0.1 mol %, about 0.5 mol %, about 1
mol %, about 2 mol %, about 3 mol %, about 4 mol %, or about 5 mol %.

[0245] In certain embodiments, the invention relates to a method of making
any one of the aforementioned dimers, according to Scheme 6a

##STR00053##

wherein X is a non-coordinating anion.

[0246] In certain embodiments, the invention relates to a method of making
any one of the aforementioned dimers, according to Scheme 6b

##STR00054##

wherein X is a non-coordinating anion.

[0247] In certain embodiments, the invention relates to a method of making
any one of the aforementioned dimers, according to Scheme 6c

##STR00055##

wherein X is a non-coordinating anion.

[0248] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the Pd(II) source is Pd(OAc)2.

[0249] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the solvent is a non-polar solvent or a
polar aprotic solvent. In certain embodiments, the invention relates to
any one of the aforementioned methods, wherein the solvent is toluene. In
certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the solvent is THF.

[0250] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the reaction takes place at from about
25° C. to about 75° C. In certain embodiments, the
invention relates to any one of the aforementioned methods, wherein the
reaction takes place at about 25° C., about 30° C., about
35° C., about 40° C., about 45° C., about 50°
C., about 55° C., about 60° C., about 65° C., about
70° C., or about 75° C.

[0251] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the reaction is substantially complete
after about 30 min, about 35 min, about 40 min, about 45 min, about 50
min, about 55 min, or about 60 min.

[0252] In certain embodiments, the invention relates to a method of making
any one of the aforementioned precatalysts, according to Scheme 7

##STR00056##

wherein

[0253] X is a non-coordinating anion; and

[0254] L is a ligand as defined above.

[0255] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the solvent is a polar aprotic solvent.
In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the solvent is THF or CH2Cl2.

[0256] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the reaction takes place at from about
10° C. to about 40° C. In certain embodiments, the
invention relates to any one of the aforementioned methods, wherein the
reaction takes place at about 15° C., about 20° C., about
25° C., about 30° C., or about 35° C.

[0257] In certain embodiments, the invention relates to any one of the
aforementioned methods, wherein the reaction is substantially complete
after about 10 min, about 15 min, about 20 min, about 25 min, about 30
min, about 35 min, about 40 min, about 45 min, about 50 min, about 55
min, about 60 min, about 65 min, about 70 min, about 75 min, about 80
min, about 85 min, or about 90 min. In certain embodiments, the invention
relates to any one of the aforementioned methods, wherein the reaction is
substantially complete after about 2 h, about 3 h, about 4 h, about 5 h,
about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, or
about 12 h.

[0258] The reactions of the present invention may be performed under a
wide range of conditions, though it will be understood that the solvents
and temperature ranges recited herein are not limitative and only
correspond to exemplary modes of the processes of the invention.

[0259] In general, it will be desirable that reactions are run using mild
conditions which will not adversely affect the reactants, the
precatalyst, or the product. For example, the reaction temperature
influences the speed of the reaction, as well as the stability of the
reactants and catalyst. The reactions will usually be run at temperatures
in the range of 25° C. to 300° C., more preferably in the
range 25° C. to 150° C.

[0260] In general, the subject reactions are carried out in a liquid
reaction medium. The reactions may be run without addition of solvent.
Alternatively, the reactions may be run in an inert solvent, preferably
one in which the reaction ingredients, including the catalyst, are
substantially soluble. Suitable solvents include ethers such as diethyl
ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether,
tetrahydrofuran, water and the like; halogenated solvents such as
chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like;
aliphatic or aromatic hydrocarbon solvents such as benzene, xylene,
toluene, hexane, pentane and the like; esters and ketones such as ethyl
acetate, acetone, and 2-butanone; polar aprotic solvents, such as
acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or
combinations of two or more solvents.

[0261] The invention also contemplates reaction in a biphasic mixture of
solvents, in an emulsion or suspension, or reaction in a lipid vesicle or
bilayer. In certain embodiments, it may be preferred to perform the
catalyzed reactions in the solid phase with one of the reactants or a
ligand anchored to a solid support.

[0262] In certain embodiments it is preferable to perform the reactions
under an inert atmosphere of a gas such as nitrogen or argon.

[0263] The reaction processes of the present invention can be conducted in
continuous, semi-continuous or batch fashion and may involve a liquid
recycle operation as desired. The processes of this invention are
preferably conducted in batch fashion. Likewise, the manner or order of
addition of the reaction ingredients, precatalyst and solvent are also
not generally critical to the success of the reaction, and may be
accomplished in any conventional fashion. In an order of events that, in
some cases, can lead to an enhancement of the reaction rate, the base,
e.g., t-BuONa, is the last ingredient to be added to the reaction
mixture.

[0264] The reaction can be conducted in a single reaction zone or in a
plurality of reaction zones, in series or in parallel or it may be
conducted batchwise or continuously in an elongated tubular zone or
series of such zones. The materials of construction employed should be
inert to the starting materials during the reaction and the fabrication
of the equipment should be able to withstand the reaction temperatures
and pressures. Means to introduce and/or adjust the quantity of starting
materials or ingredients introduced batchwise or continuously into the
reaction zone during the course of the reaction can be conveniently
utilized in the processes especially to maintain the desired molar ratio
of the starting materials. The reaction steps may be effected by the
incremental addition of one of the starting materials to the other. Also,
the reaction steps can be combined by the joint addition of the starting
materials to the metal catalyst. When complete conversion is not desired
or not obtainable, the starting materials can be separated from the
product and then recycled back into the reaction zone.

[0265] The processes may be conducted in either glass-lined, stainless
steel or similar type reaction equipment. The reaction zone may be fitted
with one or more internal and/or external heat exchanger(s) in order to
control undue temperature fluctuations, or to prevent any possible
"runaway" reaction temperatures.

[0266] Furthermore, one or more of the reactants can be immobilized or
incorporated into a polymer or other insoluble matrix by, for example,
derivativation with one or more of substituents of the aryl group.

DEFINITIONS

[0267] For convenience, before further description of the present
invention, certain terms employed in the specification, examples, and
appended claims are collected here.

[0268] The term "alkyl" refers to the radical of saturated aliphatic
groups, including straight-chain alkyl groups, branched-chain alkyl
groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl
groups, and cycloalkyl substituted alkyl groups. In preferred
embodiments, a straight chain or branched chain alkyl has 30 or fewer
carbon atoms in its backbone (e.g., C1-C30 for straight chain,
C3-C30 for branched chain), and more preferably 20 or fewer.
Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring
structure, and more preferably have 5, 6 or 7 carbons in the ring
structure.

[0269] The term "aralkyl", as used herein, refers to an alkyl group
substituted with an aryl group (e.g., an aromatic or heteroaromatic
group).

[0270] Unless the number of carbons is otherwise specified, "lower alkyl"
as used herein means an alkyl group, as defined above, but having from
one to ten carbons, more preferably from one to six carbon atoms in its
backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have
similar chain lengths but with at least two carbon atoms. Preferred alkyl
groups are lower alkyls. In preferred embodiments, a substituent
designated herein as alkyl is a lower alkyl.

[0271] The term "aryl" as used herein includes 5-, 6- and 7-membered
aromatic groups that may include from zero to four heteroatoms, for
example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan,
thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine,
pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups
having heteroatoms in the ring structure may also be referred to as "aryl
heterocycles" or "heteroaromatics". The aromatic ring can be substituted
at one or more ring positions with such substituents as described above,
for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,
cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,
phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,
sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or
heteroaromatic moieties, --CF3, --CN, or the like. The term "aryl"
also includes polycyclic ring systems having two or more cyclic rings in
which two or more carbons are common to two adjoining rings (the rings
are "fused rings") wherein at least one of the rings is aromatic, e.g.,
the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls,
aryls and/or heterocyclyls.

[0272] The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms, and dba represent
methyl, ethyl, phenyl, trifluoromethanesulfonyl,
nonafluorobutanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and
dibenzylideneacetone, respectively. Also, "DCM" stands for
dichloromethane; "rt" stands for room temperature, and may mean about
20° C., about 21° C., about 22° C., about 23°
C., about 24° C., about 25° C., or about 26° C.;
"THF" stands for tetrahydrofuran; "BINAP" stands for
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; "dppf" stands for
1,1'-bis(diphenylphosphino)ferrocene; "dppb" stands for
1,4-bis(diphenylphosphinobutane; "dppp" stands for
1,3-bis(diphenylphosphino)propane; "dppe" stands for
1,2-bis(diphenylphosphino)ethane. A more comprehensive list of the
abbreviations utilized by organic chemists of ordinary skill in the art
appears in the first issue of each volume of the Journal of Organic
Chemistry; this list is typically presented in a table entitled Standard
List of Abbreviations. The abbreviations contained in said list, and all
abbreviations utilized by organic chemists of ordinary skill in the art
are hereby incorporated by reference.

[0273] The terms ortho, meta and para apply to 1,2-, 1,3- and
1,4-disubstituted benzenes, respectively. For example, the names
1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

[0275] The term "non-coordinating anion" relates to a negatively charged
moiety that interacts weakly with cations. Non-coordinating anions are
useful in studying the reactivity of electrophilic cations, and are
commonly found as counterions for cationic metal complexes with an
unsaturated coordination sphere. In many cases, non-coordinating anions
have a negative charge that is distributed symmetrically over a number of
electronegative atoms. Salts of these anions are often soluble non-polar
organic solvents, such as dichloromethane, toluene, or alkanes.

[0276] The terms "polycyclyl" or "polycyclic group" refer to two or more
rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or
heterocyclyls) in which two or more carbons are common to two adjoining
rings, e.g., the rings are "fused rings". Rings that are joined through
non-adjacent atoms are termed "bridged" rings. Each of the rings of the
polycycle can be substituted with such substituents as described above,
as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,
ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic
moiety, --CF3, --CN, or the like.

[0277] The term "heteroatom" as used herein means an atom of any element
other than carbon or hydrogen. Preferred heteroatoms are nitrogen,
oxygen, sulfur and phosphorous.

[0278] As used herein, the term "nitro" means --NO2; the term
"halogen" designates --F, --Cl, --Br or --I; the term "sulfhydryl" means
--SH; the term "hydroxyl" means --OH; and the term "sulfonyl" means
--SO2--.

[0279] The terms "amine" and "amino" are art recognized and refer to both
unsubstituted and substituted amines, e.g., a moiety that can be
represented by the general formula:

##STR00057##

wherein R9, R10 and R'10 each independently represent a
hydrogen, an alkyl, an alkenyl, --(CH2)m--R8, or R9
and R10 taken together with the N atom to which they are attached
complete a heterocycle having from 4 to 8 atoms in the ring structure;
R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle
or a polycycle; and m is zero or an integer in the range of 1 to 8. In
preferred embodiments, only one of R9 or R10 can be a carbonyl,
e.g., R9, R10 and the nitrogen together do not form an imide.
In even more preferred embodiments, R9 and R10 (and optionally
R'10) each independently represent a hydrogen, an alkyl, an alkenyl,
or --(CH2)m--R8. Thus, the term "alkylamine" as used
herein means an amine group, as defined above, having a substituted or
unsubstituted alkyl attached thereto, i.e., at least one of R9 and
R10 is an alkyl group.

[0280] The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized
and refer to trifluoromethanesulfonyl, p-toluenesulfonyl,
methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The
terms triflate, tosylate, mesylate, and nonaflate are art-recognized and
refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester,
methanesulfonate ester, and nonafluorobutanesulfonate ester functional
groups and molecules that contain said groups, respectively.

[0281] The phrase "protecting group" as used herein means temporary
modifications of a potentially reactive functional group which protect it
from undesired chemical transformations. Examples of such protecting
groups include esters of carboxylic acids, silyl ethers of alcohols, and
acetals and ketals of aldehydes and ketones, respectively. The field of
protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.
M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York,
1991).

[0282] It will be understood that "substitution" or "substituted with"
includes the implicit proviso that such substitution is in accordance
with permitted valence of the substituted atom and the substituent, and
that the substitution results in a stable compound, e.g., which does not
spontaneously undergo transformation such as by rearrangement,
cyclization, elimination, etc.

[0283] As used herein, the term "substituted" is contemplated to include
all permissible substituents of organic compounds. In a broad aspect, the
permissible substituents include acyclic and cyclic, branched and
unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic
substituents of organic compounds. Illustrative substituents include, for
example, those described hereinabove. The permissible substituents can be
one or more and the same or different for appropriate organic compounds.
For purposes of this invention, the heteroatoms, such as nitrogen, may
have hydrogen substituents and/or any permissible substituents of organic
compounds described herein which satisfy the valencies of the
heteroatoms.

[0284] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements, CAS
version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside
cover.

EXEMPLIFICATION

[0285] The invention may be understood with reference to the following
examples, which are presented for illustrative purposes only and which
are non-limiting. The substrates utilized in these examples were either
commercially available, or were prepared from commercially available
reagents.

Example 1

Synthesis of Palladium Sulfonate Dimers

2-Aminobiphenylpalladium mesylate dimer

[0286] A 300-mL round-bottomed flask equipped with a magnetic stir bar and
fitted with a rubber septum was charged with 2-ammoniumbiphenyl mesylate
(7.89 g, 30.0 mmol, 1.00 eq) and palladium acetate (6.72 g, 30.0 mmol,
1.00 eq). The flask was evacuated and backfilled with argon (this
sequence was repeated three times), after which 120 mL anhydrous toluene
was added. The mixture was stirred at 50° C. for 45 min or until
it became milky and off-white in appearance. After cooling to room
temperature the suspension was filtered, washed with toluene (25 mL) and
diethyl ether (3×25 mL), and dried under vacuum for 24 hours to
afford the title compound as an off-white to tan solid. Yield: 10.2 g
(92%). FIG. 2.

2-Aminobiphenylpalladium ethanesulfonate dimer

[0287] A 50-mL round-bottomed flask equipped with a magnetic stir bar and
fitted with a rubber septum was charged with 2-ammoniumbiphenyl
ethanesulfonate (1.20 g, 4.30 mmol, 1.00 eq.) and palladium acetate (963
mg, 4.30 mmol, 1.00 eq). Then toluene (25 mL) was added by syringe and
the mixture was heated at 50° C. for 45 minutes or it became a
milky, off-white suspension. After cooling to room temperature the
suspension was filtered and washed with diethyl ether (3×10 mL) and
dried under vacuum to afford the title compound as a deep beige solid.
Yield: 1.61 g, 98%. FIG. 3.

2-Aminobiphenylpalladium camphorsulfonate dimer

[0288] A 50-mL round-bottomed flask equipped with a magnetic stir bar and
bitted with a rubber septum was charged with 2-aminobiphenyl (338 mg,
2.00 mmol, 1.00 eq), (±)-10-camphorsulfonic acid (464 mg, 2.00 mmol,
1.00 eq.) and palladium acetate (448 mg, 2.00 mmol, 1.00 eq). Then
toluene (20 mL) was added by syringe and the mixture was stirred at
50° C. for 45 minutes or until milky and off-white in appearance.
After cooling to room temperature the suspension was filtered and washed
with diethyl ether (3×10 mL) and dried under vacuum to afford the
title compound as a tan solid. Yield: 677 mg, 67%. FIG. 4.

2-Aminobiphenylpalladium tosylate dimer

[0289] A 24-mL test tube equipped with a magnetic stir bar and fitted with
a teflon septum was charged with 2-aminobiphenyl (169 mg, 1.00 mmol, 1.00
eq) and p-toluenesulfonic acid monohydrate (192 mg, 1.00 mmol, 1.00 eq).
The tube was sealed and then evacuated and backfilled with argon,
followed by the addition of THF (5 mL). The resulting suspension was
stirred at room temperature for 10 minutes, after which palladium acetate
(224 mg, 1.00 mmol, 1.00 eq) was added and rinsed down the walls of the
flask with the use of additional THF (2 mL). The mixture was then heated
at 50° C. for 30 min, or until it became a homogenous yellow
solution. After cooling to room temperature, the solution volume was
reduced by 75% with the aid of a rotary evaporator, after which the
product was precipitated with hexanes. The resulting solid was filtered
and dried under vacuum for 24 hours to afford the title compound as a
beige solid. Yield: 355 mg, 80%. FIG. 5.

Example 2

Synthesis of 2-Aminobiphenylpalladium Mesylate Precatalysts

2-Aminobiphenylpalladium mesylate precatalyst general procedure

[0290] A test tube, equipped with a magnetic stir bar and fitted with a
Teflon screw-cap, was charged with 2-aminobiphenylpalladium mesylate
dimer (370 mg, 0.50 mmol, 0.50 eq) and ligand (1.00 mmol, 1.00 eq). THF
or DCM (5 mL) was added by syringe and the reaction was stirred for 15
min to 1 h. The reaction progress was monitored by 31P NMR,
observing the disappearance of free ligand signal and appearance of the
precatalyst signal downfield. After completion, the reaction mixture was
transferred to a scintillation vial and the solvent was removed under
vacuum at room temperature until ˜10% remained. The residue was
then triturated with pentane. The resulting solid was isolated via
filtration and further dried under vacuum. FIG. 6.

[0291] A 300-mL round-bottomed flask equipped with a stir bar and rubber
septum was charged with μ-OMs dimer 3 (11.92 g, 15.25 mmol, 0.50 eq)
and XPhos (14.52 g, 30.5 mmol, 1.00 eq). The flask was evacuated under
vacuum and backfilled with argon (this procedure was repeated twice),
after which THF (120 mL) was added. The reaction mixture was stirred at
room temperature for 45 min. After removal of 90% of the solvent under
vacuum the product was precipitated from pentane to afford the title
compound as an off-white solid as the 1:1 THF complex. THF could be
removed by dissolving the solid in DCM and reprecipitating with pentane.
Yield: 25.5 g, 92%. FIG. 7.

[0292] FIG. 8 tabulates the % yield of various precatalysts formed using
the procedures outlined above.

Example 3

Synthesis of 2-Aminobiphenylpalladium Triflate Precatalysts

2-Aminobiphenylpalladium triflate tBuBrettPhos Precatalyst

[0293] A 250-mL round-bottomed flask equipped with a stirbar was charged
with 2-aminobiphenylpalladium chloride dimer (3.41 g, 5.5 mmol, 0.50 eq)
and silver triflate (2.82 g, 11 mmol, 1.00 eq.) and shielded from light.
Then dichloromethane (100 mL) was added and the mixture was stirred at
room temperature for 30 min. The suspension was then filtered through a
wet pad of Celite into a 500-mL round-bottomed flask equipped with a stir
bar containing tBuBrettPhos (5.33 g, 11 mmol, 1.00 eq). An additional
portion of dichloromethane (50 mL) was used to rinse the first flask and
elute the mixture through the Celite plug. The resulting mixture was
stirred at room temperature for 2 h, until becoming deep red in color.
After removing ˜90% of the solvent via rotary evaporation, pentane
(200 mL) was added to precipitate the precatalyst. The suspension was
sonicated for 30 minutes, crushed with a spatula and filtered. The
resulting solid was dried under vacuum overnight to give the title
compound as a dark orange solid. Yield: 9.59 g, 96%. FIG. 9.

Example 4

General Procedure for Catalyzed Arylation of Primary Amines

[0294] An oven-dried, resealable tube equipped with a magnetic stir bar
and Teflon septum was charged with OMsBrettPhos precatalyst (0.01-0.5 mol
%), BrettPhos (0.01-0.5 mol %) NaOt-Bu (115 mg, 1.20 mmol, 1.20 eq), aryl
halide (1.00 mmol, 1.00 eq) and amine (1.20 mmol, 1.20 eq) if they are
solids. The tube was evacuated and backfilled with argon. This process
was repeated three times. Then the aryl halide and amine were added if
they are liquid, followed by dioxane (1 mL). The reaction was heated at
100° C. and monitored by thin-layer chromatography or gas
chromatography, observing the disappearance of aryl halide. After
completion the reaction was cooled to room temperature, diluted with
ethyl acetate, and filtered through a plug of Celite. The solvent was
removed via rotary evaporation and the crude product was then purified by
flash chromatography. See FIG. 14.

Example 5

General Procedure for Catalyzed Arylation of Secondary Amines

[0295] An oven-dried resealable tube equipped with a stir bar and Teflon
septum was charged with OMsRuPhos precatalyst (0.01-1 mol %), RuPhos
(0.01-1 mol %) NaOtBu (115 mg, 1.20 mmol, 1.20 eq), aryl halide (1.00
mmol) and amine (1.20 mmol, 1.20 eq) if they are solids. The tube was
evacuated and backfilled with argon. This was repeated three times. Then
the aryl halide and amine are added if they are liquid followed by THF (1
mL). The reaction was heated at 85° C. and monitored by thin-layer
chromatography or gas chromatography, observing the disappearance of aryl
halide. After completion the reaction was cooled to room temperature,
diluted with ethyl acetate, and filtered through a plug of Celite. The
solvent was removed via rotary evaporation and the crude product was then
purified by flash chromatography. See FIG. 15.

Example 6

General Procedure for Suzuki-Miyaura Coupling of Unstable Boronic Acids

[0296] A resealable tube equipped with a magnetic stir bar and Teflon
septum was charged with OMsXPhos precatalyst (2 mol %), the aryl halide
(1 mmol) (if a solid), and the boronic acid (1.5 mmol). The tube was then
evacuated and backfilled with argon. This process was repeated three
times. Then the aryl halide (if a liquid) was added followed by THF (2
mL) and degassed 0.5 M K3PO4 solution (4 mL). The reaction was
then stirred at rt or 40° for 30 min. The reaction mixture was
diluted with water (10 mL) and ethyl acetate (10 mL) and the layers are
separated. The aqueous layer was extracted with ethyl acetate three
times. The combined organic phases are dried over magnesium sulfate,
concentrated under vacuum and purified via column chromatography. See
FIG. 16

Example 7

General Procedure for Arylation of Primary Amides

[0297] An oven-dried, resealable tube equipped with a magnetic stir bar
and Teflon septum was charged with OTf-tBuBrettPhos precatalyst (9.1 mg,
1 mol %), K3PO4 (297 mg, 1.40 mmol, 1.40 eq), aryl halide (1.00
mmol, 1.00 eq) and amide (1.20 mmol, 1.20 eq) if they are solids. The
tube was sealed and evacuated and backfilled with argon. This process was
repeated three times. Then the aryl halide and amide were added if they
are liquids, followed by tBuOH (2 mL). The reaction was heated at
110° C. and monitored by thin-layer chromatography or gas
chromatography, observing the disappearance of aryl halide. After
completion, the reaction was cooled to room temperature and diluted with
ethyl acetate and water. The phases were separated and the aqueous phase
was back extracted with ethyl acetate (2×5 mL). The combined
organic phases were dried over sodium sulfate, concentrated via rotary
evaporation and the crude product was purified by column chromatography.
See FIG. 17.

Example 8

General Procedure for Fluorination of Aryl Triflates

[0298] In a nitrogen filled glovebox an oven-dried resealable tube
equipped with a stir bar was charged with (in this order) CsF (2.0 mmol,
2.0 eq.), OTf-tBuBrettPhos precatalyst (1-5%), aryl triflate (1.0 mmol,
1.0 eq.), and toluene (5 mL). The tube was sealed with a Teflon septum
and removed from the glovebox, and the reaction mixture was stirred at
120-130° C. overnight. The reaction mixture was then allowed to
cool to room temperature, filtered through celite eluting with Et2O,
and concentrated via rotary evaporation. The crude product was purified
by flash chromatography. See FIG. 18.

[0299] A test tube, equipped with a magnetic stir bar and fitted with a
Teflon screw-cap, was charged with μ-Cl dimer (78 mg, 0.125 mmol, 0.50
eq) and KPF6 (276 mg, 1.50 mmol, 3.00 eq). The tube was sealed and
evacuated and backfilled with argon (this was repeated two times), after
which acetonitrile (3 mL) and methanol (1 mL) was added. After stirring
for 30 min, XPhos (238 mg, 0.50 mmol, 1.00 eq) was added and rinsed down
the sides of the tube with additional acetonitrile and the mixture was
stirred overnight. After completion, the reaction mixture was eluted
through celite and the solvent was removed via rotary evaporation. The
residue was then triturated with pentane. The resulting solid was
isolated via filtration and further dried under vacuum. See FIG. 19.

Example 10

Synthesis of 2-Aminobiphenylpalladium Tetrafluoroborate Precatalysts

[0300] A test tube, equipped with a magnetic stir bar and fitted with a
Teflon screw-cap, was charged with μ-Cl dimer (78 mg, 0.125 mmol, 0.50
eq) and NaBF4 (165 mg, 1.50 mmol, 3.00 eq). The tube was sealed and
evacuated and backfilled with argon (this was repeated two times), after
which acetonitrile (3 mL) and methanol (1 mL) was added. After stirring
for 30 min, XPhos (238 mg, 0.50 mmol, 1.00 eq) was added and rinsed down
the sides of the tube with additional acetonitrile and the mixture was
stirred overnight. After completion, the reaction mixture was eluted
through celite and the solvent was removed via rotary evaporation. The
residue was then triturated with pentane. The resulting solid was
isolated via filtration and further dried under vacuum. See FIG. 20.

Example 11

Synthesis of N-Phenyl-2-aminobiphenylpalladium Mesylate Precatalysts

N-phenyl-[1,1'-biphenyl]-2-ammonium mesylate

[0301] A 50 mL round-bottomed flask equipped with a stir bar was charged
with 2-(N-phenyl)aminobiphenyl (1.09 g, 4.4 mmol, 1.00 eq) and diethyl
ether (25 mL). Methanesulfonic acid (285 μL, 4.4 mmol, 1.00 eq) was
added dropwise and the reaction mixture was stirred for 30 minutes. The
solvent was then removed via rotary evaporation and the product was
further dried under vacuum to yield the title compound as a green oil.

N-Phenyl-2-aminobiphenylpalladium mesylate dimer

[0302] A 24 mL screw-top tube equipped with a stir bar was charged with
palladium acetate (1.00 g, 4.48 mmol, 1.00 eq) and a solution of
N-phenyl-[1,1'-biphenyl]-2-ammonium mesylate (1.48 g, 4.48 mmol, 1.00 eq)
in THF (10 mL). The reaction mixture was stirred at 50° C. for 15
minutes, until a yellow precipitate formed. After cooling to room
temperature the solid was filtered and washed with diethyl ether
(2×10 mL) and pentane (2×10 mL) and further dried under
vacuum to afford the title compound as a yellow solid. Yield: 1.4 g, 65%.

[0303] A test tube, equipped with a magnetic stir bar and fitted with a
Teflon screw-cap, was charged with N-Phenyl-2-aminobiphenylpalladium
mesylate dimer (446 mg, 0.50 mmol, 0.50 eq) and XPhos (476 mg, 1.00 mmol,
1.00 eq), followed by DCM (5 mL). The reaction was stirred at room
temperature for 1 h. After completion, the reaction mixture was
transferred to a scintillation vial and the solvent was removed under
vacuum at room temperature. The residue was then triturated with pentane.
The resulting solid was isolated via filtration and further dried under
vacuum to provide the title compound as a yellow solid. See FIG. 21.

Example 12

Synthesis of N-Methyl-2-aminobiphenylpalladium Mesylate Precatalyst

N-methyl-[1,1'-biphenyl]-2-ammonium mesylate

[0304] A 50-mL round-bottomed flask equipped with a stir bar was charged
with 2-(N-methyl)aminobiphenyl (600 mg, 3.25 mmol, 1.00 eq) and diethyl
ether (25 mL). Methanesulfonic acid (212 μL, 3.25 mmol, 1.00 eq) was
added dropwise and the reaction mixture was sonicated for 30 minutes and
then stirred for 30 minutes. The resulting solid was filtered and further
dried under vacuum to provide the title compound as a white solid. Yield:
578 mg, 61%.

N-methyl-2-aminobiphenylpalladium mesylate dimer

[0305] A 24-mL screw-top tube equipped with a stir bar was charged with
palladium acetate (448 mg, 2.00 mmol, 1.00 eq) and a solution of
N-methyl-[1,1'-biphenyl]-2-ammonium mesylate (578 mg, 2.00 mmol, 1.00 eq)
in THF (10 mL). The reaction mixture was stirred at 50° C. for 15
minutes, until the solution became yellow in color. After cooling to room
temperature the solvent was removed via rotary evaporation and the
resulting residue was treated with diethyl ether (25 mL) to precipitate a
beige solid. The resulting solid was filtered and further dried under
vacuum. Yield: 530 mg, 69%.

[0306] A test tube, equipped with a magnetic stir bar and fitted with a
Teflon screw-cap, was charged with N-methyl-2-aminobiphenylpalladium
mesylate dimer (96 mg, 0.125 mmol, 0.50 eq) and XPhos (119 mg, 0.25 mmol,
1.00 eq), followed by DCM (5 mL). The reaction was stirred at room
temperature for 1 h. After completion, the reaction mixture was
transferred to a scintillation vial and the solvent was removed under
vacuum at room temperature. The residue was then triturated with pentane.
The resulting solid was isolated via filtration and further dried under
vacuum to provide the title compound as an off-white solid.

INCORPORATION BY REFERENCE

[0307] All of the U.S. patents and U.S. patent application publications
cited herein are hereby incorporated by reference.

EQUIVALENTS

[0308] Those skilled in the art will recognize, or be able to ascertain
using no more than routine experimentation, many equivalents to the
specific embodiments of the invention described herein. Such equivalents
are intended to be encompassed by the following claims.

Patent applications by Nicholas C. Bruno, California, MD US

Patent applications by Stephen L. Buchwald, Newton, MA US

Patent applications in class And carbon bonded directly to the heavy metal

Patent applications in all subclasses And carbon bonded directly to the heavy metal